The goal of this application is to determine if the carotid body chemoreceptors are involved in insulin-mediated sympathoexcitation. This project provides an excellent intellectual and a robust laboratory training opportunity for an F32 application focusing on integrative physiological functions regulated by the carotid bodies. The carotid chemoreceptors are polymodal sensors known for their oxygen-sensing capabilities and recent experimental evidence suggests they may also respond to insulin. [By systematically examining insulin-sensing capabilities of the carotid chemoreceptors using novel, parallel approaches in both animals and humans, the proposed studies will determine the role of the carotid bodies as integrated sensors influencing insulin-mediated sympathoexcitation. Insulin-mediated changes in carotid chemoreceptor activity may provide a potential mechanism for the pathophysiology of a series of metabolic disorders including hypertension, insulin resistance, and sleep apnea. Specific Aim 1 will examine the effect of insulin on carotid chemoreceptor activation ex vivo. Using an isolated rat carotid body preparation, we will directly measure changes in carotid body afferent activity in response to insulin exposure. We hypothesize insulin will result in an increase in carotid sinus nerve activity. We also hypothesize insulin will increae the sensory response to hypoxia, and any insulin-mediated changes in afferent nerve activity will be blunted with hyperoxia. Specific Aim 2 will determine the contribution of the carotid chemoreceptors to insulin-mediated autonomic and cardiorespiratory responses in healthy humans. In Aim 2a, we will compare changes in muscle sympathetic nerve activity (MSNA) with hyperinsulinemia under normoxic and hyperoxic conditions (to inhibit carotid body chemoreceptor- mediated responses). In Aim 2b, we will compare changes in MSNA, ventilation, and carotid body chemosensitivity (hypoxic ventilatory response, HVR) with hyperinsulinemia under control conditions and during a low-dose infusion of dopamine (to inhibit carotid body chemoreceptor-mediated responses). We hypothesize insulin will result in an increase in MSNA, ventilation, and chemoreceptor sensitivity in humans. We also hypothesize the effect of hyperinsuilnemia on MSNA, ventilation, and HVR will be blunted during hyperoxia and/or low-dose dopamine infusion.] We propose novel, high impact, and translational studies investigating the role of the carotid bodies as integrated sensors of circulating insulin that influence sympathetic and cardiorespiratory reflexes. [The research team assembled, combined with the extensive resources at the Mayo Clinic and University of Chicago, provides the optimal training environment to complete studies in this area. Importantly, basic physiological data will be collected under tightly controlled conditions in both ex vivo animal and human studies to systematically examine acute effects of circulating insulin levels that are critical for future targeted studies in patient populations.]